REVIEWS
The use of brachytherapy in the treatment ofnonmelanoma skin cancer: A review
Murad Alam, MD, MSCI,a,b,c Shivani Nanda, BS,a Bharat B. Mittal, MD,d Natalie A. Kim, BA,a
and Simon Yoo, MDa,b,c
Chicago, Illinois
From
an
Fe
Nort
fu
Conf
Repr
D
16
Publ
0190
ª 20
doi:1
Nonmelanoma skin cancers can be treated by various modalities, including electrodessication andcurettage, excisional techniques, and radiation. In selected cases, radiation may be preferable to surgery.When radiation is an option, brachytherapy, a form of radiation therapy that places the radiation sourceclose to the area to be treated, may have advantages relative to conventional external beam radiation inparticular patients. After brachytherapy, recurrence rates for nonmelanoma skin cancers are low, especiallyfor small, superficial lesions, with good to excellent functional and cosmetic results. This article reviews theindications, efficacy, and adverse effects of brachytherapy in the treatment of nonmelanoma skin cancers.( J Am Acad Dermatol 2011;65:377-88.)
Key words: basal cell carcinoma; brachytherapy; interstitial brachytherapy; nonmelanoma skin cancer;squamous cell carcinoma; surface-mold brachytherapy.
Abbreviations used:
BCC: basal cell carcinomaHDR: high-dose rateIr: iridiumLDR: low-dose rateNMSC: nonmelanoma skin cancerSCC: squamous cell carcinoma
Nonmelanoma skin cancers (NMSCs) are themost common forms of cancer in theCaucasian population, with basal cell carci-
nomas (BCCs) representing approximately 75% ofNMSCs and cutaneous squamous cell carcinomas(SCCs) comprising 25%.1 The standard of care forBCCs and SCCs is typically local destruction orsurgical removal, including electrodessication andcurettage, elliptical excision, or Mohs micrographicsurgery. Small, well-circumscribed, or superficialtumors may be treated with cryotherapy, photody-namic therapy, or imiquimod.2 In selected patients,radiation, including external beam radiation orbrachytherapy, is an appropriate and effectiveoption.
TREATMENT OF NMSC WITHRADIOTHERAPY
Historically, external radiotherapy, consisting ofsuperficial x-rays or electron therapy, has been a
the Departments of Dermatology,a OtolaryngologyeHead
d Neck Surgery,b Surgery,c and Radiation Oncology,d
inberg School of Medicine, Northwestern University.
hwestern University Department of Dermatology provided
nding.
licts of interest: None declared.
int requests: Murad Alam, MD, MSCI, Department of
ermatology, Northwestern University, 676 N St Clair, Suite
00, Chicago, IL 60611. E-mail: [email protected].
ished online April 18, 2011.
-9622/$36.00
10 by the American Academy of Dermatology, Inc.
0.1016/j.jaad.2010.03.027
commonly used treatment for NMSCs. With theadvent of precise surgical treatments, such as Mohsmicrographic surgery, which offers tissue-sparingtumor removal, the use of radiation for NMSCs hasdeclined. The reported 5-year control rates for NMSCtreatment with external beam radiation are verygood, varying from 80% to 92% for SCC and BCC,respectively; from 93% to 80% for primary andrecurrent NMSC, respectively3; and approximating79% for tumors of the ear.4 However, even these verygood control rates are substantially inferior to the98% to 99% 5-year cure rates for primary BCC byMohs micrographic surgery,5 although part of thisdifference could be ascribed to selection bias. Inaddition, ionizing radiation can penetrate deeply,potentially injuring adjacent tissue and organs caus-ing brain and bone necrosis.6,7 Skin changes associ-ated with radiation, such as atrophy, telangiectasia,and pigmentation, may worsen with time.
Finally, given the abundance of facial NMSCassociated with use of radiation for acne treatment,dermatologists have been understandably con-cerned about the risk of inducing new precancerousand cancer lesions in the radiation field,8 particularly
377
J AM ACAD DERMATOL
AUGUST 2011
378 Alam et al
in younger patients. Radiation for skin cancer hasbeen shown to increase the likelihood of subsequentBCC and SCC by approximately 3-fold9; radiation hasalso been shown to increase the risk of subsequentmelanoma10; and elevated incidence of skin cancerhas been shown to increase the risk of secondprimary nonskin cancers.11 Although there is no
CAPSULE SUMMARY
d In brachytherapy, the radioactive sourceis applied on (ie, surface mold) or placedinto (ie, interstitial) the body, versus inexternal beam radiotherapy, in which theradiation source is at a distance from thepatient and aimed at the site to betreated.
d Although surgery is the first-linetreatment for nonmelanoma skin cancer,radiotherapy can be indicated inselected cases. When radiotherapy ischosen, brachytherapy may be a goodchoice for shallow, widespread lesions, orlesions at anatomic sites (eg, hand, fullscalp) that lie immediately abovestructures vulnerable to irradiation.
d Brachytherapy provides minimal dosedelivery to surrounding healthy tissue,thus enabling good functional andcosmetic results.
d Brachytherapy appears to be mosteffective for small, primary, and/orsuperficial squamous cell carcinomasand basal cell carcinomas, which can alsobe treated with surgery or external beamradiotherapy.
clear consensus regardingthe age at which patientsshould receive radiationtherapy for NMSC, late adult-hood, perhaps around age 60years, may be a reasonablethreshold.
That being said, there re-main indications for radia-tion treatment of NMSC.Some tumors are truly inop-erable, either because of thepatient’s inability to physi-cally undergo the removalor the reconstruction, or be-cause of the size and ana-tomic location of the tumor.In addition, elderly or infirmpatients with limited func-tional status but relativelylarge tumors who can theo-retically tolerate surgery maynonetheless prefer a nonin-vasive treatment, such as ra-diation. When surgery hasbeen attempted, but marginclearance is not possible, ad-juvant radiotherapy may alsobe indicated; this may espe-cially be the case for diffuseor neurotropic SCCs, espe-cially those of the scalp, lip,
and ear. Finally, although long-term cosmesis aftersurgery has steadily improved as the quality ofreconstructions has increased over time, in selectedcases, radiotherapy offers superb cosmetic results aswell.In the United States, most radiation of skin canceris by teletherapy, or external beam radiation, inwhich an external source of radiation, commonlycomprising photons or electrons, is aimed at thetarget lesion on the body. Teletherapy has beenimproved or adapted over the years, and is a versatiletechnology that can successfully treat many skincancers.12,13 Indeed, advances in teletherapy dis-placed the popularity of another form of radiationtherapy, brachytherapy, approximately 20 years ago;now brachytherapy is experiencing somewhat of
a resurgence, especially in Europe, and even in theUnited States.14
Brachytherapy for treatment of NMSCBrachytherapy, derived from the Greek ‘‘brachy,’’
or short distance, entails placement of radioactivesources directly onto or into target tissues.15
Brachytherapy is an ancienttechnique, which has beenused to treat malignanciessince the discovery of radiumby Curie and Becquerel.11
Treatment of skin cancerwas first attempted in 1899,and until about 1940, radiumapplication was the favoredmethod.16,17 For the first fewdecades, thin-walled con-tainers plated with RaSO4
and inert metals were ap-plied to the skin in directcontact therapy. Startingabout 1930, this approachwas gradually replaced byradium puncture, with 2 to 7radium needles loaded with5 to 10 mg of radium appliedto the surface of the tumor atintervals of 5 mm for 4 to 5hours. Ten-year control rateswith direct contact therapyand radium puncture werereported to be 73.8% and84%, respectively. Radiumbrachytherapy was so popu-lar it was routinely used fornoncancerous dermatologiclesions, such as hemangi-omas.17 By the mid-1940s,
brachytherapy declined in favor as a modality fortreatment of skin lesions and was gradually replacedby x-rays.18 In more recent times, brachytherapy hascome to be used more commonly for treatment ofhead and neck, prostate, cervical, and endometrialcancers, but use for skin cancers is gradually increas-ing worldwide.19
From a technical standpoint, placement of theradioactive sources in modern brachytherapy maybe into a body cavity (intracavity), across a tissueboundary into a contained space (transluminal), intobody tissues (interstitial), or on the body surface(surface-mold technique). In the surface-mold tech-nique, custom molds are created from impressions ofthe tumor surface, fitted with radioactive isotopes,and then applied to the tumor.20
Table I. Comparison of dose delivery with commonbrachytherapy techniques
LDR 192Ir MDR HDR
Dose rate Low Medium High
Duration per treatment 2-6 d 1 d MinutesDuration of treatment course 2-6 d 1 d 3-5 wkAvailability (internationally) 11 e eEase of optimization e e 1
Dose per treatment, Gy 60 40 0.18-.7*No. of fractions 1 1 7-35Total dose as sole modality, Gy 60 40 35-50*
HDR, High-dose rate; Ir, iridium; LDR, low-dose rate; MDR, medium-
dose rate.
Adapted with permission from Lippincott Williams & Wilkins
(http://lww.com).35
*Common regimens may include 20 to 35 fractions of 180 to 200 cGy
each in daily or twice-daily treatments; 5 fractions of 700 cGy for
total dose of 35 Gy; or 10 fractions of 500 cGy for total dose of 50 Gy.
J AM ACAD DERMATOL
VOLUME 65, NUMBER 2
Alam et al 379
Since the mid-1960s, radioactive sources are nolonger implanted directly into the patient, as thispractice exposes the radiation oncologist and staff tounacceptable levels of irradiation. Instead, nonra-dioactive tubes, catheters, or other applicators arefirst implanted into the target site, and then sourcesare ‘‘afterloaded’’ into this apparatus.16 Manual after-loading has now been replaced by remote after-loading, which permits the operator to remain in ashielded site.
Implants associated with brachytherapy may bepermanent or temporary.21 In either case, the tech-nique minimizes unwanted dose delivery to nearbyhealthy but radiation-sensitive organs, such as thebrain.19 Thus, brachytherapy can be performed onthe scalp and other areas where traditional externalradiotherapy may be less safe.22,23
Permanent brachytherapy implants emit radiationat very-low-dose rates (LDR), equivalent to less than0.4 Gy/h for the lifetime of the radioactive isotope.Typically, iodine-125 is used in such implants be-cause of its emission of relatively low mean energies.In contrast, temporary implants (Table I) are associ-ated with greater variation in dose rates, with LDRimplants delivering 0.4 to 2 Gy/h, over durationsfrom 24 to 144 hours in an inpatient setting; medium-dose-rate devices delivering 2 to 12 Gy/h; and high-dose-rate (HDR) emitters delivering more than 12Gy/h15 (Table I). The most commonly used isotopefor temporary implantation is iridium-192 (192Ir),which has a half-life of 74.2 days and emits g rayswith a mean energy of 380 keV. Other g-emittingisotopes used for temporary implantation, especiallyin the past, include cobalt and cesium.20
A single treatment of LDR brachytherapy canrequire 3 to 5 days, requiring radiation protection
for those who are in contact with the patient for theduration. Conversely, an HDR brachytherapy treat-ment can be completed in 1 to 30 minutes, usually onan outpatient basis. However, HDR brachytherapy ismore likely to cause damage to surrounding normaltissue than is LDR brachytherapy. To avoid suchcomplications, when HDR brachytherapy is per-formed, the total dose is commonly divided overa few or as many as 30 to 40 sessions, every 1 to28 days.
Surface-mold brachytherapySurface-mold brachytherapy (Tables II and III) is
commonly used for the treatment of well-circumscribed, superficial tumors. Molds are con-structed from pliable materials, such as silicone orpolymethyl-methacrylate, and are fitted to the tumorsurface (Figs 1 and 2). Radioactive sources are thenloaded into the mold in such as a manner as todistribute uniform, radioactive dosage throughoutthe tumor volume (Figs 3 and 4). Surface-moldbrachytherapy is often delivered at HDR (\12 Gy/h).
LDR brachytherapy with surface molds has beenstudied in retrospective studies and case series. Inone retrospective case-control study, the cosmeticoutcome was compared for 15 patients treated forBCC of the face with gold grain Elastoplast molds(Beiersdorf, Birmingham, England) and 15 patientstreated for the same indication with fractionatedsuperficial x-ray.24 The tumors in the brachytherapyarm had received total doses of 60 to 65 Gy during a7-day application, and all of the case and controltumors had been treated more than 10 years ago.Superior long-term cosmesis was observed in thebrachytherapy group. This was ascribed to the rapiddecrease in brachytherapy dose beyond the super-ficial tissues. In addition, it was hypothesized that x-ray treatment may be relatively more prone to inducevery late skin and subcutis adverse effects thanbrachytherapy. A notable case series described thetreatment of several eyelid tumors, including twoneglected BCCs on the cusp of orbital invasion.25 Forthese lesions, LDR brachytherapy with a 15-mmdiameter gold shield was used as an alternative toexenteration and external radiation. In particular, aniodine-125 plaque was applied to the outside of theshield, thus allowing protection of the globe whilepermitting irradiation of the target lesion with 50 Gyto a 5-mm depth. Two-year follow-up indicated norecurrence. Studies on the use of surface-mold HDRbrachytherapy for NMSCs have included prospectiveand retrospective cohort studies along with casereports. Most studies have evaluated the use ofg-emitting isotopes such as 192Ir, whereas at leasttwo studies explored the use of a mixed b-g
Table II. Adverse events reported after brachytherapy
Study Adverse eventseacute Adverse eventselong term
Avril et al31 112/173 Dyspigmentation and telangiectasia 69/173 Scar9/173 Necrosis1/173 Cataract1/173 Lacrimal duct stenosis*
Berridge and Morgan24 Unknown 10/15 Slight atrophy, pigmentation change,some hair loss
5/15 Patchy atrophy, moderate telangiectasia,total hair loss
Conill et al33 24/24 Erythema, edema None reportedConill et al32 54/54 Mucositis 1/54 Achromia and fibrosisDebois28 Dyschromia, telangiectasia None reportedGuix et al1 136/136 Erythema 4/136 Radiation necrosis
14/136 UlcerationLee et al27 5/5 Desquamation, erythema, or ulceration None reported
1/5 AlopeciaOzyar and Gurdalli23 None reported None reportedShields et al25 8/8 Mild postoperative discomfort and tissue
edema limits eye movementNone reported
Sedda et al26 53/53 Erythema None reportedBleeding (only large lesions)
Semrau et al22 1/1 Erythema, ulceration, bleeding None reportedSomanchi et al6 25/25 Desquamation, crusting, erythema 1/25 Radiation necrosis
17/25 Skin atrophy, telangiectasia, alopeciaSvoboda et al7 26/106 Moist reaction 6/53 Pigmentation changes, atrophy
32/106 Erythema, dry desquamationRio et al30 97/97 Inflammatory exudative desquamation 4/34 Epiphora
3/34 Pruritus1/34 Impairment of eyelid aperture
Rudoltz et al29 1/1 Erythema, moist desquamation None reported
*Adverse events for this study are for all radiotherapy patients, of whom 55% were brachytherapy patients.
J AM ACAD DERMATOL
AUGUST 2011
380 Alam et al
isotopeeeither rhenium-188 or holmium-166.26,27
HDR brachytherapy studies have investigated itsuse on NMSCs located in areas such as the nose,eyelid, ear, and back of the hands that may bedifficult to treat surgically or may benefit from thespecial features of brachytherapy, such as the abilityto confine radiation to a superficial treatment area.
A series of prospective cohort studies evaluatingthe efficacy of NMSC treatment with 192Ir HDRsurface-mold brachytherapy found good posttreat-ment cosmesis and low recurrence rates up to 5 yearslater. Relatively smaller lesions were associated withhigher rates of tumor control and better cosmeticresults compared with larger lesions. Radiating 136patients with facial NMSCs, Guix et al1 noted a 5-yearremission rate of 99% for primary tumors (n = 73) and87% for recurrent lesions (n = 63). Notably, serialbiopsies and dermatologic examinations were notperformed to confirm these remission rates.Cosmesis was assessed by subjective and objectivemeasurements (eg, absence of edema, alopecia,hypopigmentation, hyperpigmentation, fibrosis,scars, telangiectasia, and late effects on normal
tissue) at 6- and 12-month follow-up visits.Reportedly, 133 of 136 patients had favorable cos-mesis, defined as minimal to no treatment sequelaeat the 6-month follow-up visit. The remaining 2% ofpatients, all of whom had initial cancer lesions largerthan 4 cm, experienced radiation necrosis in normaltissue. However, the report failed to specify theextent to which normal tissue had been damaged.1
Svoboda et al7 treated 96 primary skin neoplasms (9Bowen disease, 11 SCC, 76 BCC) at various anatomiclocations. Results indicated tumor regression and norecurrence in all but 4 cases. All 4 recurrent tumorswere BCCs with an initial diameter greater than 2 cmand a depth greater than 3 mm. Based on theseresults, surface-mold brachytherapy appears to haveefficacy for small, primary NMSCs, but larger tumorsare likely to recur and injury to normal tissues canoccur. HDR surface-mold brachytherapy has alsobeen associated with low risk of recurrence andgood cosmesis in studies of NMSC at functionally andcosmetically important sites such as the nose andhand. Debois28 reported the use of cesium-137surface-mold brachytherapy on 370 primary lesions
Table III. Summary of previous studies of brachytherapy for nonmelanoma skin cancer
Study Site studied Lesion type Modality Treatment time
Dosage (cGy)/
fractions
Follow-up
(mo)
Recurrence
rate
Avril et al31 Face BCC (347) LDR interstitial 165 h 5700-9600/1 48 8/95Berridge and Morgan24 Face BCC (30/30) LDR surface mold 168 h 6000-6500/1 120 (minimum) UnknownConill et al33 Eyelid SCC (4/24)
BCC (19/24)Adenocarcinoma (1/24)
LDR interstitial 54-55 h (total) 4000 43 (mean) 2/24
Conill et al32 Lip SCC (52/54)BCC (2/54)
LDR interstitial 86 h 6000-6500/1 96 (mean) 2/54
Debois28 Nose Epidermoid (60/370)BCC (300/370)Other (10/370)
HDR surface mold 48 h (total) 2400 [36 11/368
Guix et al1 Face SCC (34/136)BCC (102/136)
HDR surface mold (117/136)HDR Brock applicator
(19/136)
3-8 min/session 6000-6500/33-36(\4 cm)
7500-8000/10([4 cm)
60 3/136
Lee et al27 Various SCC (3/5)BCC (1/5)Bowen (1/5)
HDR surface patch 30 min-1 h (total) 5000 8-20 0/5
Ozyar and Gurdalli23 Scalp BCC (1/1) HDR surface mold Not stated 4050/multiple 72 0Rio et al30 Face SCC (88/97)
BCC (9/97)LDR interstitial 74-79 h 5000-6500 55 (median) 10/97
Rudoltz et al29 Forearm,back of hand
SCC (1/1) HDR surface mold 30 min/session 6000/30 7 0
Sedda et al26 Various SCC (37/53)BCC (16/53)
HDR surface resin 15 min-2 h/session 4000-6000/1-3 51 (mean) 0/53
Semrau et al22 Scalp SCC (1/1) HDR surface mold Not stated 6600/[33 24 0Shields et al25 Eyelid BCC (2/8)
Adenoid cysticcarcinoma (4/8)
Conjunctival melanoma(1/8)
Metastatic carcinoma (1/8)
LDR plaque 96 h 5000/1 24 (BCC only) 0/2
Somanchi et al6 Back of hand,fingers
SCC (25/25) HDR surface mold Not stated 4000-4500/8 60 (mean) 1/25
Svoboda et al7 Various Metastases (10/106)Bowen (9/106)SCC (11/106)BCC (76/106)
HDR surface mold Up to 5 min/session 1200-5000/1-15 9.6 (mean) 4/106
BCC, Basal cell carcinoma; HDR, high-dose rate; LDR, low-dose rate; SCC, squamous cell carcinoma.
JA
MA
CA
DD
ER
MA
TO
L
VO
LU
ME
65,N
UM
BER
2
Ala
met
al
381
Fig 1. Polymethyl-methacrylate mold constructed overface mask based on impression of tumor area. Cathetersare for transmission of radioactive material, in this casefractionated high-dose-rate brachytherapy. Reproducedwith permission from Elsevier from Guix et al.1
Fig 2. Simulation radiograph of applicator in Fig 1. Thisconfirms placement of catheters, which are in parallel andevenly spaced. Reproduced with permission from Elsevierfrom Guix et al.1
Fig 3. Schematic diagram showing predicted radioactivedose distribution around applicator in Fig 1. Dose falls offrapidly as distance from catheters increases. Reproducedwith permission from Elsevier from Guix et al.1
Fig 4. Autoradiograph of applicator in Fig 1 showing dosedistribution during administration of 50 cGy. Hot spot(lower left corner) is artifact caused by film being flat andapplicator being curved. Reproduced with permissionfrom Elsevier from Guix et al.1
J AM ACAD DERMATOL
AUGUST 2011
382 Alam et al
(300 BCC, 60 ‘‘epidermoid,’’ 10 other) of the nose.A reported recurrence rate of 3% (11/368) at a 3-yearfollow-up may have been an underestimate becauseof possible ascertainment bias and lack of furtherfollow-up. Unlike most other investigators, Debois28
reported more recurrences in tumors of smallerdiameter (\2 cm).1,7 This aberrant outcome in thestudy of Debois28 may be a result of the absolutepreponderance of small tumors (87%) in this study,and not to any proportionately greater risk ofrecurrence of smaller tumors. As the authors failedto characterize the subtype of the treated BCCs, it isnot clear to what extent recurrence may have beenassociated with tumor subtype rather than size.Another site-specific study treated 25 patients forSCCs on the back of the hand and found one case ofrecurrence and one of radiation necrosis, the latter
during treatment of a large tumor. Functional mea-sures used to compare treated and nontreatedhands included grip strength, joint mobility, finetouch, and 2-point discrimination. The differencesacross the two groups were not statistically signif-icant.6 As with previously discussed studies, thesestudies suggest that HDR brachytherapy can induceprolonged remission with few peripheral tissueeffects in relatively small, well-demarcated NMSC;long-term cure was not shown, and objective orunbiased measures of postoperative cosmesis re-main lacking.
Surface-mold brachytherapy has also been usedfor multiple, recurrent tumors with vast and irregularsurface areas. Rudoltz et al29 used HDR surface-moldbrachytherapy for multiple recurrent SCCs on the
J AM ACAD DERMATOL
VOLUME 65, NUMBER 2
Alam et al 383
forearm of one patient and two case reports used asurface-mold helmet for SCCs21 and BCCs23 on thescalp. Erythema, ulceration, moist desquamation, orbleeding were reported, but follow-up in all casesrevealed no short-term recurrence, providing pre-liminary evidence for the efficacy of HDR surfacemolds on extensive, recurrent lesions.
At least 2 studies have evaluated HDR brachy-therapy using b-emitting isotopes, which may poseless risk to nearby healthy tissue.25 Furthermore,radiation therapy with b-emitting isotopes usuallyrequires 1 to 3 treatments visits, versus many moretreatments when g-emitters are used. In a study bySedda et al,26 43 of 53 patients with recurrent NMSCsrequired only one treatment with rhenium-188, ab-emitter, whereas the remaining patients withthicker lesions needed up to 3 treatments each.Mean dose declined from 120 Gy to less than 20 Gyat depths greater than 2 mm, and it is unclear whysome deeper tumors regressed or whether thisregression was merely superficial, with residualdeep tumor.26 Indeed, a study of 5 patients withholmium-166, another b-emitting radionuclide,showed that radiation dosage at depths of 2 mmand beyond was inadequate for treatment ofNMSCs.27 Because of the small number of studieson b-emitting isotopes, their efficacy in the treatmentof NMSC, especially deep and infiltrating lesions,remains unclear.
Compilation of these results indicates high localremission rates26,27 after surface-mold brachytherapyof NMSC at various anatomic locations. However,recurrent tumors, tumors of greater depth ([2 mm),and tumors of greater diameter ([2 cm) appear tohave a higher failure rate because the dosimetryconstraints of brachytherapy result in a sharp declineof radiation dose with increasing depth. Larger,infiltrative lesions also require higher total dosesand numbers of treatments, with total doses of up to8000 cGy fractionated over a large number of treat-ment sessions. Although use of b-emitting isotopesrequired fewer sessions, efficacy was compromisedfor deeper lesions. The most common reportedcomplications of surface-mold brachytherapy in-cluded erythema (77%), desquamation (65%), andulceration (14%). Cosmetic and functional resultswere evaluated subjectively by blinded6 or un-blinded29 raters. Objective measures included thepresence of late radiation effects such as alopecia,telangiectasia, skin atrophy, pigmentation disorders,and scarring.1,6,30 Functional measures such aspain,30 or range of motion of joints,6 were alsoevaluated. Overall, cosmetic and functional resultswere good, with better results observed for smallertumors.1
Interstitial brachytherapyInterstitial brachytherapy is an invasive means of
internal radiation therapy in which radioactive seedsor wires are placed directly within the tissues at thetarget site. Unlike external radiotherapy, which re-quires prolonged treatment times of up to 6 weeks,interstitial brachytherapy requires shorter treatmenttimes of as little as 80 hours. Significantly, interstitialbrachytherapy may be used in areas, such as theeyelid, where the creation of the precise surface-mold required for surface-mold brachytherapy maybe technically infeasible.
The efficacy of interstitial brachytherapy on NMSChas been evaluated primarily through one random-ized controlled trial, and additional prospective andretrospective cohort studies focusing on faciallesions. The single randomized controlled trial com-pared treatment efficacy and cosmetic outcomes byassigning 174 patients with primary BCC to surgery,and another 173 with similar presentation to radio-therapy, mostly (55% these 173) interstitial LDRbrachytherapy with 57 to 76 Gy total dose deliveredover a mean of 6.9 days. Four-year recurrence rateswere 0.7% for surgery (95% confidence interval:0.1%-3.9%) and 8.8% for brachytherapy (95% confi-dence interval: 4.3%-17.1%). Good cosmesis wasobtained in 87% of patients treated with surgeryand 69% of those treated with radiation.31
A controlled retrospective cohort study of 88 BCCand 9 SCC of the nose, periorbital area, and earcompared interstitial LDR for patients previouslyuntreated and those who had earlier received sur-gery. Total doses were 52 to 55 Gy over 74 to 79hours, and 5-year disease-free survival was 91% and80% in the untreated and previously treated patients,respectively.30 A retrospective cohort study of 52SCCs and 2 BCCs of the lip treated with 192Ir inter-stitial LDR at a mean total dose of 61.5 Gy over 86.4hours reported a local control rate of 98% at meanfollow-up of 7 years.32 This control rate was signif-icantly higher than that noted by several previousinvestigations of lip tumors with interstitial LDRbrachytherapy. A prospective cohort study exam-ined outcomes of 19 primary BCCs and 4 primarySCC of the eyelids, with a collective mean diameterof 1.3 cm, treated with 192Ir interstitial LDR with meantotal dose of 40 Gy over 55 hours. At mean follow-upof 43 months, the local control rate was 91.6%, withgood functional results.33
Lower rates of recurrence are seen in NMSCtumors less than 2 cm in diameter and in superficialNMSC tumors not exceeding 2 mm in depth.30,33
Interstitial brachytherapy is generally well toleratedby patients. Acute complications after treatmentinclude inflammatory exudative desquamation
Fig 5. Acrylic resin helmet specially constructed for treat-ment of wide area on scalp. In this case, high-dose-ratebrachytherapy with remote afterloading was used. Repro-duced with permission from Elsevier from Ozyar andGurdalli.23
J AM ACAD DERMATOL
AUGUST 2011
384 Alam et al
(80%), erythema (20%), and edema (20%). Sequelaeare usually more pronounced for larger tumors, andwhen treatment has entailed a high total dose, alarger fractionated dose, or a higher dose rate.33 Inthe few studies available, functional and cosmeticresults were graded by a single, unblinded examinerfor the presence of skin deformity, pigmentationdisorders, telangiectasia, and skin atrophy. Goodcosmetic and functional results were reported basedon this potentially biased assessment, with the mostsevere complications involving impaired eyelid ap-erture.30 Overall, interstitial brachytherapy may beadvantageous for the treatment of small, superficiallesions of NMSC.
DISCUSSIONIndications for external beam radiation andbrachytherapy
Radiation has a role in the treatment of NMSC inselected cases. In the United States, external beamradiation will likely continue to be the modality ofchoice when radiation is required, but brachyther-apy may be a useful alternative when the need arises.The primary benefit of brachytherapy comparedwith external beam radiation therapy is its ability todeliver radiation to the target tissue with less injury tosurrounding normal-appearing skin. Specifically,brachytherapy may be preferable at certain anatomicsites. Full-scalp irradiation for SCC with brachyther-apy may thus have a lower risk of excessive brainirradiation than external beam radiation because theintensity of surface-mold brachytherapy drops offrapidly away from the source (Fig 5). Likewise,treatment of NMSC of the hand with brachytherapymay reduce the risk to underlying tendons and bone,and subcutaneous fibrosis that limits dexterity. Othervery large and irregular skin areas that are repletewith numerous NMSCs may benefit from custom-mold or interstitial brachytherapy that conforms tothe surface.29
That being said, external beam radiotherapy is aversatile modality that can be adapted to successfullytreat most any skin cancer. Moreover, in the UnitedStates, expertise in brachytherapy has lagged behindthat in external beam radiation, which may thus bethe preferred choice at many centers. Because of therapid drop-off in brachytherapy intensity away fromeach radioactive source, and the difficulty in design-ing custom molds and applicators to precisely matchvarious skin surfaces, there are inherent challengeswith this therapy in ensuring homogeneous doseapplication, conformality, and target coverage. Deepand thick lesions of NMSC can be treated by3-dimensional conformal teletherapy more effec-tively than with brachytherapy.
Benefits of low-dose versus high-dosebrachytherapy
Benefits of high-dose brachytherapy comparedwith low-dose34,35 include the short duration oftreatment, which minimizes the risk that the appli-cator will move or become misaligned with thetarget. HDR may be preferred by patients becauseit is an outpatient treatment, and does not requireprolonged bed rest confined in a room; this avoid-ance of an inpatient stay can also result in significantcost reduction. A technical benefit of HDR is optimi-zation, which means the dwell times of the radioac-tive source at various locations within the applicatorcan be precisely modified and managed.
However, HDR is biologically more toxic thanLDR,34,35 in that the degree of damage to tumor cellsrelative to the damage to normal tissue cells (ie, thetherapeutic ratio) is lower for HDR than LDR.Damage to both tumor and normal cells increaseswith dose rate, but the increase in injury to healthycells is proportionately greater. To compensate forthis, HDR treatments may be fractionated into 5 ormore sessions, whereas LDR usually requires 1 or 2sessions. Also, because of the complexity and speedof HDR, and the potential for failure in the devicethat moves the radiation source (eg, source does notretract), errors can occur that result in very highradiation doses to patients. Finally, although HDRmay not require a hospital stay, it can requirerelatively more personnel, and expensive hardwaresuch as various applicators and sophisticated HDRafterloading equipment.
Fig 6. Orbital plaque made of lead to shield globe (A) thatbears on its outside surface iodine-125 seeds (B) designedto irradiate adjacent orbital tumor. Reproduced withpermission from Shields et al.25
J AM ACAD DERMATOL
VOLUME 65, NUMBER 2
Alam et al 385
Limitations in the efficacy of brachytherapyThere are, however, significant limitations in the
use of brachytherapy for treatment of even selectedNMSCs. Specifically, the tumors that respond bestwith the lowest recurrence rates are primary,superficial (\2 mm deep), and small (\2 cm indiameter). Common findings indicate a greaterrecurrence rate for lesions greater than 2 cm indiameter regardless of the mode of brachytherapyused. Moreover, most studies have found thatadequate radiation dosage with brachytherapy can-not be delivered at depths much greater than 2mm, making the treatment of infiltrative tumorsimpractical. Sufficient dose delivery for deep tu-mors would require excessive radiation exposuretime and dose to the skin. Although a single study1
has reported adequate dose distribution to depthsup to 5 mm using surface-mold HDR brachyther-apy, these results have not been replicated. Inshort, the types of tumors brachytherapy has beenshown to treat effectively are also the same tumorsthat are easily removed surgically or could betreated with external beam radiation. It is unclearto what extent large, thick, neglected tumors onelderly or frail patients may be amenable to brach-ytherapy. Thinner tumors, such as eyelid tumorsand widespread shallow areas of skin carcinogen-esis, may be better targets for brachytherapy (Figs 6and 7).
Local control, cure, and long-term disease-freesurvival
Secondly, although remission rates after brachy-therapy are reported to be high, the reportedcontrol rates are not necessarily cures. Publishedstudies7,26,29 evaluating the treatment of NMSC withbrachytherapy have usually followed up patientsfor less than 2 years, with the longest reportedfollow-up period lasting 6 years in one casestudy.23 However, studies have reported an in-creased risk of NMSC recurrence for up to 10years.36 Consequently, the long-term use of brach-ytherapy remains to be established. The concern, ofcourse, is that incompletely treated tumors may notonly recur, but may also enlarge and threatenstructures over time, especially if their deep com-ponent eludes eradication. To the extent that radi-otherapy for NMSC, including brachytherapy, isusually reserved for older patients, long-termdisease-free survival data can be difficult to obtain.On the other hand, it is quite possible that currentand future technical improvements in brachyther-apy, especially HDR brachytherapy, may lead tohigher long-term control rates than previouslypossible.
Tolerability and adverse events associated withbrachytherapy
Brachytherapy for NMSCs has been said to be welltolerated by patients. This treatment modality is espe-cially useful for areas, such as the back of the hand orthe scalp, where there is concern about radiation doseto the underlying structures, such as tendons orbrain. Brachytherapy has the benefit of localizinghigh radiation dosage to near the site of the implants,so deeper penetrating radiation injury is avoided.1,7,26
In general, good cosmetic functional results areachieved, and local adverse events are mild to mod-erate. Nonetheless, common reported acute reactionsassociated with brachytherapy include erythema(79%), ulceration (14%), and desquamation (68%).
Fig 7. Application of plaque in Fig 6 to eye (A) and after itis affixed with sutures, with patient looking ahead (B). Inthis case, tumor was adenoid cystic carcinoma of lacrimalgland. Reproduced with permission from Shields et al.25
J AM ACAD DERMATOL
AUGUST 2011
386 Alam et al
Operator safetyBrachytherapy involves potential risks of radia-
tion exposure to medical personnel involved intreatment. LDR is associated with secondary radia-tion risk because the duration of treatment isprolonged for days, and HDR, because radiationsource is of high intensity. Especially for LDR, remoteafterloading techniques, whereby nonradioactiveimplantation devices are first placed within thetumor and subsequently mechanically loaded withradioactive sources, are often used to enhanceoperator safety.
Patient selection: cosmesis and functionalstatus
Although brachytherapy has been shown to beassociated with good posttreatment cosmesis, pa-tients seeking optimal cosmesis may still opt for
surgical excision or Mohs micrographic surgery.Indeed, given the subjectivity of measurements ofcosmesis and the dearth of side-by-side comparisonsof brachytherapy, external beam radiation, and sur-gical reconstruction, it is difficult to make a strongassertion as to the relative cosmetic benefits of thesetreatment modalities. In one study, facial BCCs wererandomized to be treated with either surgery orradiotherapy (interstitial brachytherapy, superficialcontactherapy involving delivery of low-energy dos-ages at close proximity to the target site, andconventional radiotherapy). Upon a 4-year follow-up, blinded, observer-rated cosmetic results werebetter for lesions treated with surgery for all tumorsites on the face, except the nose, for which thedifference in cosmetic results did not reach statisticalsignificance.37 But not much can be concluded froma single study, and further studies with unbiased andideally objective outcome measures are needed.
Similarly, although brachytherapy can be usefulfor elderly, infirm patients unable to tolerate surgery,a minimal level of functional status is probablynecessary before embarking on radiation therapyof any type. Specifically, brachytherapy is bestapplied only to patients who are able to providebaseline self-care needs. Patients with disordersresulting in periods of confusion or delirium maynot be ideal candidates. When selecting patients forbrachytherapy, special attention should be given topatients’ ability to follow guidelines regarding radi-ation exposure.
ConclusionsAlthough brachytherapy is an alternate radiation
modality that may be useful for treatment of selectedNMSCs that may benefit from radiation, furtherresearch is needed to clarify the extent to whichthis modality can effectively treat the large and deeptumors typically not amenable to surgery (Table IV).Rater-blinded and objective assessments may alsobetter clarify the extent to which cosmesis andfunctional outcomes with brachytherapy comparefavorably or unfavorably with postsurgical out-comes. Longer-term follow-up and prospective con-trolled studies may similarly yield importantinformation regarding the long-term cure rates asso-ciated with the latest techniques of LDR and HDRbrachytherapy for NMSC, rather than the short- tomedium-term control rates now available. Finally,more data are needed on the differential cure rates ofsubtypes of BCC, and of B6CC versus SCC.
Brachytherapy is not a benign or inexpensivemodality. Even in the best hands, local tissue des-quamation and ulceration can occur, and typicallymultiple treatment sessions are required. It is also
Table IV. Brachytherapy study type and level of evidence
Study Journal N(subject/lesions) Study type Level of evidence29
Avril et al31 Br J Cancer 347/347 Randomized control trial 1Berridge and Morgan24 Clin Oncol (R Coll Radiol) 30/30 Case-control study 4Conill et al33 Int J Radiat Oncol Biol Phys 23/24 Prospective cohort study 5bConill et al32 Clin Transl Oncol 54/54 Retrospective cohort study 5bDebois28 J Belge Radiol 370/370 Prospective cohort study 5bGuix et al1 Int J Radiat Oncol Biol Phys 136/136 Prospective cohort study 5bLee et al27 J Nucl Med 5/5 Prospective cohort study 5bOzyar and Gurdalli23 Int J Radiat Oncol Biol Phys 1/multiple Case report 5cRio et al30 Int J Radiat Oncol Biol Phys 97/97 Retrospective cohort study 5bRudoltz et al29 J Am Acad Dermatol 1/multiple Case report 5cSedda et al26 Clin Exp Dermatol 53/53 Single group pre/post test
prospective cohort study5b
Semrau et al22 Br J Dermatol 1/multiple Case report 5cShields et al25 Ophthal Plast Reconstr Surg 2/2 Case series 5cSomanchi et al6 Clin Oncol (R Coll Radiol) 25/25 Retrospective cohort study 5bSvoboda et al7 Int J Radiat Oncol Biol Phys 76/106 Prospective cohort study 5b
J AM ACAD DERMATOL
VOLUME 65, NUMBER 2
Alam et al 387
certainly worth considering to what extent brachy-therapy should be kept in reserve, as a treatment oflast resort for lesions that have previously faileddermatologic treatment, including surgery and ex-ternal beam radiation.
That being said, when radiation is considered inthe treatment of resistant, recurrent, and inoperableskin tumors, and tumors in patients who cannottolerate excisional surgery or reconstruction, brach-ytherapy may have a role. In such circumstances,there is no ideal therapy, and brachytherapy is farfrom a panacea, but it may be appropriate in selectedcircumstances, especially when there is widespreadtumor or tumor at anatomic sites overlying vulnera-ble neurovascular or musculoskeletal structures.Further research may improve the use of brachy-therapy for NMSC treatment, and provide informa-tion that clarifies the precise indications for suchtreatment. Large-scale randomized controlled trialshave yet to be conducted to assess the efficacy andsafety of brachytherapy, and to compare it directlywith external beam therapy.
REFERENCES
1. Guix B, Finestres F, Tello J, Palma C, Martinez A, Guix J, et al.
Treatment of skin carcinomas of the face by high-dose-rate
brachytherapy and custom-made surface molds. Int J Radiat
Oncol Biol Phys 2000;47:95-102.
2. Hansen S, Mathes S, Young D. Skin and subcutaneous tissue.
In: Brunicardi FC, Andersen DK, Billiar TR, Dunn DL, Hunter JG,
Matthews JB, et al, editors. Schwartz’s principles of surgery.
8th ed. New York: McGraw Hill Companies; 2005.
3. Locke J, Karimpour S, Young G, Lockett MA, Perez CA.
Radiotherapy for epithelial skin cancer. Int J Radiat Oncol
Biol Phys 2001;51:748-55.
4. Silva JJ, Tsang RW, Panzarella T, Levin W, Wells W. Results of
radiotherapy or epithelial skin cancer of the pinna: the
Princess Margaret Hospital experience, 1982-1993. Int J Radiat
Oncol Biol Phys 2000;47:451-9.
5. Rubin AI, Chen EH, Ratner D. Basal cell carcinoma. N Engl
J Med 2005;353:2262-9.
6. Somanchi B, Stanton A, Webb M, Loncaster J, Allan E, Muir L.
Hand function after high dose rate brachytherapy for squa-
mous cell carcinoma of the skin of the hand. Clin Oncol (R Coll
Radiol) 2008;20:691-7.
7. Svoboda V, Kovarik J, Morris F. High dose-rate microselectron
molds in the treatment of skin tumors. Int J Radiat Oncol Biol
Phys 1995;31:967-72.
8. Fangman W, Cook J. Postradiation sarcoma: case report and
review of the potential complications of therapeutic ionizing
radiation. Dermatol Surg 2005;31:966-72.
9. Licher MD, Karagas MR, Mott LA, Spencer SK, Stukel TA,
Greenberg ER. Therapeutic ionizing radiation and the inci-
dence of basal cell carcinoma and squamous cell carcinoma.
Arch Dermatol 2000;136:1007-11.
10. Guerin S, Duphy A, Anderson H, Shamsaldin A, Svahn-Tapper
G, Moller T, et al. Radiation dose as risk factor for malignant
melanoma following childhood cancer. Eur J Cancer 2003;39:
2379-86.
11. Cantwell MM, Murray LJ, Catney D, Donnelly D, Autier P,
Boniol M, et al. Second primary cancers in patients with skin
cancer: a population-based study in Northern Ireland. Br
J Cancer 2009;100:174-7.
12. Solan MJ, Brady LW. Skin. In: Halperin EC, Perez CA, Brady LW,
editors. Perez and Brady’s principles and practice of radiation
oncology. 5th ed. Philadelphia (PA): Lippincott, Williams &
Wilkins; 2008. pp. 690-701.
13. Ang KK, Weber RS. Cutaneous carcinoma. In: Gunderson LL,
Tepper JE, editors. Clinical radiation oncology. 2nd ed. London:
Churchill Livingstone; 2006. pp. 853-63.
14. Montemaggi P, Guerrieri P, Federico M, Mortellaro G. Clinical
applications of brachytherapy: low-dose-rate and pulse-dose-
rate. In: Halperin EC, Perez CA, Brady LW, editors. Perez and
Brady’s principles and practice of radiation oncology. 5th ed.
Philadelphia (PA): Lippincott, Williams & Wilkins; 2008. pp.
476-539.
15. Williamson JF, Brenner DJ. Physics and biology of brachyther-
apy. In: Halperin EC, Perez CA, Brady LW, editors. Perez and
Brady’s principles and practice of radiation oncology. 5th ed.
J AM ACAD DERMATOL
AUGUST 2011
388 Alam et al
Philadelphia (PA): Lippincott, Williams & Wilkins; 2008. pp.
423-75.
16. Hansen PB, Jensen MS. Late results following radiotherapy
of skin cancer. Acta Oncol 1968;7:307-20.
17. Furst CJ, Lundell M, Holm L- E. Radiation therapy of heman-
giomas, 1909-1959. Acta Oncol 1987;26:33-6.
18. Guadagnolo BA, Ang KK, Ballo MT. The skin. In: Moss WT,
Brand WN, Battifora H, editors. Radiation oncology: rationale,
technique, results. St Louis (MO): CV Mosby Co; 1979. pp.
52-82.
19. Martinez AA. Brachytherapy. In: Gunderson LL, Tepper JE,
editors. Clinical radiation oncology. 2nd ed. London: Churchill
Livingstone; 2006. pp. 255-82.
20. Devlin PM, editor. Brachytherapy applications and techniques.
Philadelphia: Lippincott Williams & Wilkins; 2007.
21. Pathi S, Dorigo O. Radiation therapy for gynecologic cancers. In:
DeCherney AH, Nathan L, editors. Current diagnosis and treat-
ment obstetrics and gynecology. 10th ed. New York: McGraw-
Hill Co; 2007.
22. Semrau S, Kunz M, Baggesen K, Vogel H, Fietkau R, Gross G, et al.
Successful treatment of field cancerization of the scalp by
surface mould brachytherapy. Br J Dermatol 2008;159:753-5.
23. Ozyar E, Gurdalli S. Mold brachytherapy can be an optional
technique for total scalp irradiation. Int J Radiat Oncol Biol
Phys 2002;54:1286.
24. Berridge JK, Morgan DA. A comparison of late cosmetic results
following two different radiotherapy techniques for treating
basal cell carcinoma. Clin Oncol (R Coll Radiol) 1997;9:400-2.
25. Shields JA, Shields CL, Freire JE, Brady LW, Komarnicky L.
Plaque radiotherapy for selected orbital malignancies: prelim-
inary observations; the 2002 Montgomery lecture, part 2.
Ophthal Plast Reconstr Surg 2003;19:91-5.
26. Sedda A, Rossi G, Cipriani C, Carrozzo M, Donati P. Dermato-
logical high-dose-rate brachytherapy for the treatment of
basal and squamous cell carcinoma. Clin Exp Dermatol 2008;
33:745-9.
27. Lee JD, Park KK, Lee M, Kim E, Rhim KJ, Lee JT, et al. Radionuclide
therapy of skin cancers and Bowen’s disease using a specially
designed skin patch. J Nucl Med 1997;38:697-702.
28. Debois J. Cesium-137 brachytherapy for epithelioma of the
skin of the nose: experience with 370 patients. J Belge Radiol
1994;77:1-4.
29. Rudoltz M, Perkins R, Luthmann R, Fracke T, Green T, Eaglstein
F, et al. High-dose-rate brachytherapy with a custom-surface
mold to treat recurrent squamous cell carcinomas of the skin
of the forearm. J Am Acad Dermatol 1998;38:1003-5.
30. Rio E, Bardet E, Ferron C, Peuvrel P, Supiot S, Campion L, et al.
Interstitial brachytherapy of periorificial skin carcinomas of the
face: a retrospective study of 97 cases. Int J Radiat Oncol Biol
Phys 2005;63:753-7.
31. Avril MF, Auperin A, Margulis A, Gerbaulet A, Duvillard P,
Benhamou E, et al. Basal cell carcinoma of the face: surgery or
radiotherapy? Results of a randomized study. Br J Cancer 1997;
76:100-6.
32. Conill C, Verger E, Marruecos J, Vargas M, Biete A. Low dose
rate brachytherapy in lip carcinoma. Clin Transl Oncol 2004;9:
251-4.
33. Conill C, Sanchez-Reyes A, Molla M, Vilalta A. Brachytherapy
with 192Ir as treatment of carcinoma of the tarsal structure of
the eyelid. Int J Radiat Oncol Biol Phys 2004;59:1326-9.
34. Thomasden B, Das R. The physics and dosimetry of high-dose-
rate brachytherapy. In: Halperin EC, Perez CA, Brady LW,
editors. Perez and Brady’s principles and practice of radiation
oncology. 5th ed. Philadelphia (PA): Lippincott, Williams &
Wilkins; 2008. pp. 540-59.
35. Nag S, Scruggs GR. Clinical aspects and applications of high-
dose-rate brachytherapy. In: Halperin EC, Perez CA, Brady LW,
editors. Perez and Brady’s principles and practice of radiation
oncology. 5th ed. Philadelphia (PA): Lippincott, Williams &
Wilkins; 2008. pp. 560-82.
36. Hadorn DC, Baker D, Hodges JS, Hicks N. Rating the quality of
evidence for clinical practice guidelines. J Clin Epidemiol 1996;
49:749-53.
37. Petit JY, Avril MF, Margulis A, Chassagne D, Gerbaulet A,
Duvillard P, et al. Evaluation of cosmetic results of a random-
ized trial comparing surgery and radiotherapy in the treat-
ment of basal cell carcinoma of the face. Plast Reconstr Surg
2000;105:2544-51.
